Rhinocort Aqua

CLINICAL PHARMACOLOGY

Mechanism of Action

Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid
activity and weak mineralocorticoid activity. In standard in vitro and
animal models, budesonide has approximately a 200-fold higher affinity for the
glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency
than cortisol (rat croton oil ear edema assay). As a measure of systemic activity,
budesonide is 40 times more potent than cortisol when administered subcutaneously
and 25 times more potent when administered orally in the rat thymus involution
assay. The clinical significance of this is unknown.

The activity of RHINOCORT AQUA Nasal Spray is due to the parent drug, budesonide.
In glucocorticoid receptor affinity studies, the 22R form was two times as active
as the 22 S epimer. In vitro studies indicated that the two forms of
budesonide do not interconvert.

The precise mechanism of corticosteroid actions on inflammation in seasonal and perennial allergic rhinitis is not well known. Inflammation is an important component in the pathogenesis of seasonal and perennial allergic rhinitis. Corticosteroids have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in seasonal and perennial allergic rhinitis.

Pharmacodynamics

A 3-week clinical study in seasonal rhinitis, comparing RHINOCORT Nasal Inhaler, orally ingested budesonide, and placebo in 98 patients with allergic rhinitis due to birch pollen, demonstrated that the therapeutic effect of RHINOCORT Nasal Inhaler can be attributed to the topical effects of budesonide.

HPA Axis Effects

The effects of RHINOCORT AQUA (budesonide) Nasal Spray on adrenal function have been evaluated in several clinical trials. In a four-week clinical trial, 61 adult patients who received 256 mcg daily of RHINOCORT AQUA (budesonide) Nasal Spray demonstrated no significant differences from patients receiving placebo in plasma cortisol levels measured before and 60 minutes after 0.25 mg intramuscular cosyntropin. There were no consistent differences in 24-hour urinary cortisol measurements in patients receiving up to 400 mcg daily. Similar results were seen in a study of 150 children and adolescents aged 6 to 17 with perennial rhinitis who were treated with 256 mcg daily for up to 12 months.

After treatment with the recommended maximal daily dose of RHINOCORT AQUA (budesonide) Nasal
Spray (256 mcg) for seven days, there was a small, but statistically significant
decrease in the area under the plasma cortisol-time curve over 24 hours (AUC0-24h)
in healthy adult volunteers.

A dose-related suppression of 24-hour urinary cortisol excretion was observed after administration of RHINOCORT AQUA (budesonide) Nasal Spray doses ranging from 100-800 mcg daily for up to four days in 78 healthy adult volunteers. The clinical relevance of these results is unknown.

Pharmacokinetics

Absorption

After intranasal administration of a single dose of RHINOCORT AQUA (budesonide) Nasal Spray
(128 mcg), the mean peak plasma concentration of approximately 0.3 nmol/L occurs
about 0.5 hours post-dose. Compared to an intravenous dose, approximately 34%
of the delivered intranasal dose reaches the systemic circulation, most of which
is absorbed through the nasal mucosa. While budesonide is well absorbed from
the GI tract, the oral bioavailability of budesonide is low (~10%) primarily
due to extensive first pass metabolism in the liver.

Distribution

The volume of distribution of budesonide was approximately 2-3 L/kg. It was 85-90% bound to plasma proteins. The volume of distribution for the 22R epimer is almost twice that of the 22 S epimer. Protein binding was constant over a concentration range (1-100 nmol/L) achieved with, and exceeding, recommended doses of RHINOCORT AQUA Nasal Spray. Budesonide showed little or no binding to corticosteroid binding globulin. Budesonide rapidly equilibrated with red blood cells in a concentration independent manner with a blood/plasma ratio of about 0.8.

Metabolism

In vitro studies with human liver homogenates have shown that budesonide
is rapidly and extensively metabolized. Two major metabolites formed via cytochrome
P450 (CYP) isoenzyme 3A4 (CYP3A4)-catalyzed biotransformation have been isolated
and identified as 16α-hydroxyprednisolone and 6p-hydroxybudesonide. The
corticosteroid activity of each of these two metabolites is less than 1% of
that of the parent compound. No qualitative difference between the in vitro
and in vivo metabolic patterns have been detected. Negligible metabolic
inactivation was observed in human lung and serum preparations.

Excretion/Elimination

The 22R form of budesonide was preferentially cleared by the liver with systemic clearance of 1.4 L/min vs. 1.0 L/min for the 22S form. The terminal half-life, 2 to 3 hours, was the same for both epimers and was independent of dose. Budesonide was excreted in urine and feces in the form of metabolites. Approximately 2/3 of an intranasal radiolabeled dose was recovered in the urine and the remainder in the feces. No unchanged budesonide was detected in the urine.

Specific Populations

Geriatric

The pharmacokinetics of RHINOCORT AQUA (budesonide) Nasal Spray in geriatric patients have
not been specifically studied.

Pediatric

Following administration of RHINOCORT AQUA (budesonide) Nasal Spray, the time to reach peak drug concentrations and plasma half-life were similar in children and in adults. Children had plasma concentrations approximately twice those observed in adults due primarily to differences in weight between children and adults.

Gender

No specific pharmacokinetic study has been conducted to evaluate the effect of gender on budesonide pharmacokinetics. However, following administration of 400 mcg of RHINOCORT AQUA (budesonide) Nasal Spray to 7 male and 8 female volunteers in a pharmacokinetic study, no major gender differences in the pharmacokinetic parameters were found.

Race

No specific study has been undertaken to evaluate the effect of race on budesonide
pharmacokinetics.

Nursing Mothers

The disposition of budesonide when delivered by oral inhalation from a dry
powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months
was studied in eight lactating women with asthma from 1 to 6 months postpartum.
Systemic exposure to budesonide in these women appears to be comparable to that
in non-lactating women with asthma from other studies. Breast milk obtained
over eight hours post-dose revealed that the maximum concentration of budesonide
for the 400 and 800 mcg doses was 0.39 and 0.78 nmol/L, respectively, and occurred
within 45 minutes after dosing. The estimated oral daily dose of budesonide
from breast milk to the infant was approximately 0.007 and 0.014 mcg/kg/day
for the two dose regimens used in this study, which represents approximately
0.3% to 1% of the dose inhaled by the mother. Budesonide levels in plasma samples
obtained from five infants at about 90 minutes after breastfeeding (and about
140 minutes after drug administration to the mother) were below quantifiable
levels ( < 0.02 nmol/L in four infants and < 0.04 nmol/L in one infant) [see
Use In Specific Populations, Nursing Mothers].

Renal or Hepatic Impairment

The pharmacokinetics of budesonide have not been investigated in patients with renal impairment. Reduced liver function may affect the elimination of corticosteroids. The pharmacokinetics of budesonide were affected by compromised liver function as evidenced by a doubled systemic availability after oral ingestion. The relevance of this finding to intranasally administered budesonide has not been established.

Cimetidine: At recommended doses, cimetidine, a nonspecific inhibitor
of CYP enzymes, had a slight but clinically insignificant effect on the pharmacokinetics
of oral budesonide.

Animal Toxicology and/or Pharmacology

Budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide
produced fetal loss, decreased pup weights, and skeletal abnormalities at a
subcutaneous dose of 25 mcg/kg in rabbits (approximately 2 times the maximum
recommended daily intranasal dose in adults on a mcg/m2 basis) and
at a subcutaneous dose of 500 mcg/kg in rats (approximately 16 times the maximum
recommended daily intranasal dose in adults on a mcg/m2 basis). No
teratogenic or embryocidal effects were observed in rats when budesonide was
administered by inhalation doses up to 250 mcg/kg (approximately 8 times the
maximum recommended daily intranasal dose in adults on a mcg/m2 basis).

Clinical Studies

The therapeutic efficacy of RHINOCORT AQUA (budesonide) Nasal Spray has been evaluated in placebo-controlled clinical trials of seasonal and perennial allergic rhinitis of 3-6 weeks duration.

The number of patients treated with budesonide in these studies was 90 males and 51 females aged 6-12 years and 691 males and 694 females 12 years and above. The patients were predominantly Caucasian.

Overall, the results of these clinical trials showed that RHINOCORT AQUA (budesonide) Nasal Spray administered once daily provides statistically significant reduction in the severity of nasal symptoms of seasonal and perennial allergic rhinitis including runny nose, sneezing, and nasal congestion.

An improvement in nasal symptoms may be noted in patients within 10 hours of first using RHINOCORT AQUA (budesonide) Nasal Spray. This time to onset is supported by an environmental exposure unit study in seasonal allergic rhinitis patients that demonstrated that RHINOCORT AQUA (budesonide) Nasal Spray led to a statistically significant improvement in nasal symptoms compared to placebo by 10 hours. Further support comes from a clinical study of patients with perennial allergic rhinitis which demonstrated a statistically significant improvement in nasal symptoms for both RHINOCORT AQUA (budesonide) Nasal Spray and for the active comparator (mometasone furoate) compared to placebo by 8 hours. Onset was also assessed in this study with peak nasal inspiratory flow rate and this endpoint failed to show efficacy for either active treatment. Although statistically significant improvements in nasal symptoms compared to placebo were noted within 8-10 hours in these studies, about one half to two thirds of the ultimate clinical improvement with RHINOCORT AQUA (budesonide) Nasal Spray occurs over the first 1-2 days, and maximum benefit may not be achieved until approximately 2 weeks after initiation of treatment.